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Purpose Several risk factors have been claimed to predict the progression of clinically high grade T1 bladder tumors. However, these factors are not specific enough to define which patients should be treated immediately with radical cystectomy. Therefore, it is critical to identify molecular markers that can help provide individualized, risk stratified decision making. Our main goal was to evaluate the role of total p63, p53 and ΔNp63 expression in cases of clinically high grade T1 bladder cancer progression. Materials and Methods Total p63, p53 and ΔNp63 expression was analyzed by immunohistochemistry in 134 clinically high grade T1 tumors. We assessed clinical progression to muscle invasive disease or radical cystectomy as a patient outcome end point. Survival analysis was done for recurrence-free, progression-free, disease specific and overall survival. Results A total of 132 patients (98.5%) underwent repeat transurethral resection. Cases of early progression (less than 3 months) were excluded from study to avoid under staging. Of the tumors 90 (67.2%) showed ΔNp63 expression loss. During a median followup of 62.1 months 19 patients (14.2%) progressed to muscle invasive disease. The progression rate was 21.1% in patients with tumors characterized by ΔNp63 loss but no progression was observed in those with tumors with ΔNp63 expression (p <0.001). There was no difference in the number of patients who underwent repeat transurethral resection, had associated carcinoma in situ, showed lymphovascular invasion or received followup intravesical bacillus Calmette-Guérin courses. Conclusions ΔNp63 expression is a favorable prognostic factor in clinically high grade T1 bladder cancer. This marker identifies patients at low risk for progression who could benefit from conservative therapy with transurethral bladder tumor resection and bacillus Calmette-Guérin, avoiding over treatment with immediate radical cystectomy. [ABSTRACT FROM AUTHOR]

Purpose: The expression of desmogleins (DSGs), which are known to be crucial for establishing and maintaining the cell-cell adhesion required for tissue integrity, has been well characterized in the epidermis and hair follicle; however, their expression in other epithelial tissues such as prostate is poorly understood. Although downregulation of classical cadherins, such as E-cadherin, has been described in prostate cancer tissue samples, the expression of desmogleins has only been previously reported in prostate cancer cell lines. In this study we characterized desmoglein expression in normal prostate tissues, and further investigated whether Desmoglein 2 (DSG2) expression specifically can serve as a potential clinical prognostic factor for patients diagnosed with primary prostate cancer. Experimental Design: We utilized immunofluorescence to examine DSG2 expression in normal prostate (n = 50) and in a clinically well-characterized cohort of prostate cancer patients (n = 414). Correlation of DSG2 expression with clinico-pathological characteristics and biochemical recurrence was analyzed to assess its clinical significance. Results: These studies revealed that DSG2 and DSG4 were specifically expressed in prostatic luminal cells, whereas basal cells lack their expression. In contrast, DSG1 and DSG3 were not expressed in normal prostate epithelium. Further analyses of DSG2 expression in prostate cancer revealed that reduced levels of this biomarker were a significant independent marker of poor clinical outcome. Conclusion: Here we report for the first time that a low DSG2 expression phenotype is a useful prognostic biomarker of tumor aggressiveness and may serve as an aid in identifying patients with clinically significant prostate cancer. [ABSTRACT FROM AUTHOR]

Cre-loxp mediated conditional knockout strategy has played critical roles for revealing functions of many genes essential for development, as well as the causal relationships between gene mutations and diseases in the postnatal adult mice. One key factor of this strategy is the availability of mice with tissue- or cell type-specific Cre expression. However, the success of the traditional molecular cloning approach to generate mice with tissue specific Cre expression often depends on luck. Here we provide a better alternative by using bacterial artificial chromosome (BAC)-based recombineering to insert iCreERT2 cDNA at the ATG start of the Upk2 gene. The BAC-based transgenic mice express the inducible Cre specifically in the urothelium as demonstrated by mRNA expression and staining for LacZ expression after crossing with a Rosa26 reporter mouse. Taking into consideration the size of the gene of interest and neighboring genes included in a BAC, this method should be widely applicable for generation of mice with tissue specific gene expression or deletions in a more specific manner than previously reported. [ABSTRACT FROM AUTHOR]

Purpose: After encouraging results from 2 clinical trials performed at our institution to test intravesical taxane based chemotherapy for bacillus Calmette-Guérin refractory, nonmuscle invasive bladder cancer we designed a study to identify molecular markers linked to the optimal response to such treatment modality. Materials and Methods: Included in the institutional review board approved study were 32 patients with nonmuscle invasive, bacillus Calmette-Guérin refractory bladder cancer who received intravesical taxane chemotherapy, that is docetaxel or nanoparticle albumin-bound paclitaxel. Immunophenotype analysis on tissue samples obtained before intravesical taxane therapy was done using a panel of molecular markers, including Ki-67, p53, and the microtubule associated proteins tau and stathmin. Results: Increased total tau (cytoplasmic and nuclear) and stathmin expression before intravesical taxane therapy was significantly associated with decreased recurrence-free survival (p <0.0001 and 0.007, respectively). A tau positive phenotype was an independent prognostic factor for recurrence-free survival on multivariate analysis (HR 15.66, 95% CI 2.68–91.71, p = 0.002). Neither the proliferation index assessed by Ki-67 expression nor p53 status was significantly associated with recurrence-free survival. Conclusions: Assessment of tau and stathmin protein expression should be considered to select patients before intravesical taxane based chemotherapy for nonmuscle invasive, bacillus Calmette-Guérin refractory bladder cancer since those who have tumors with low tau/stathmin protein expression show a better response to therapy. [ABSTRACT FROM AUTHOR]

Summary: To identify regulatory drivers of prostate cancer malignancy, we have assembled genome-wide regulatory networks (interactomes) for human and mouse prostate cancer from expression profiles of human tumors and of genetically engineered mouse models, respectively. Cross-species computational analysis of these interactomes has identified FOXM1 and CENPF as synergistic master regulators of prostate cancer malignancy. Experimental validation shows that FOXM1 and CENPF function synergistically to promote tumor growth by coordinated regulation of target gene expression and activation of key signaling pathways associated with prostate cancer malignancy. Furthermore, co-expression of FOXM1 and CENPF is a robust prognostic indicator of poor survival and metastasis. Thus, genome-wide cross-species interrogation of regulatory networks represents a valuable strategy to identify causal mechanisms of human cancer. [ABSTRACT FROM AUTHOR]